DESCRIPTION (Adapted from the applicant's description) Narcolepsy-cataplexy is a sleep disorder affecting 0.05% of the general population in the US. The development of narcolepsy involves environmental factors on a specific genetic background. The importance of environmental factors can be illustrated by the fact that 25-31% of monozygotic twins reported in the literature are discordant for narcolepsy. One of the predisposing genetic factors is located in the MHC DQ region. Eighty-five to 100 percent of all patients share a specific HLA allele, DQB1+0602 versus 12-38% of the general population in various ethnic groups. Genetic factors other than HLA are also likely to be involved. Even if genuine multiplex families are rare, 1-2% of the first degree relative of a patient with narcolepsy are affected by the disorder. These investigators have found a few multiplex families with numerous affected members and no apparent haplotype linkage with HLA. Studies using a canine model of the disorder also illustrate the importance of non MHC genes in disease predisposition. In this model, narcolepsy is transmitted as a single autosomal recessive trait (canarc-1) unlinked with MHC class II polymorphisms. A solid linkage marker for canarc-1 has been identified (current LOD score=15.3 at 0% recombination). In this project, a positional cloning approach will be used in both canines and humans to isolate novel narcolepsy susceptibility genes. Forty-eight multiplex families with narcolepsy-cataplexy and a microsatelite marker genome scanning experiment will be used to determine human genomic segments containing narcolepsy susceptibility genes. In canines, a large insert (BAC) library will first be constructed. This resource will be used to build genomic contigs and to develop new polymorphic markers around the previously identified canine narcolepsy gene marker. They will then saturate susceptibility regions in both canines and humans with polymorphic markers to narrow down the region containing candidate narcolepsy genes. Candidate genes will then be isolated and tested using high throughput genomic sequencing and other molecular techniques until disease susceptibility genes are identified. This group believes this approach will reveal the cause of narcolepsy and open new therapeutic avenues for the disorder.